Many diseases could benefit from long-term endogenous production of therapeutic molecules, including proteins. We propose to investigate the possibility of using implantation of genetically modified autologous mesenchymal stem cells (MSCs) for sustained delivery of enzymes with therapeutic potential. Our overall goal is to test this therapeutic approach by evaluating the ability of appropriate MSCs implanted in the eye to prevent retinal degeneration associated with lysosomal enzyme deficiencies. This goal will be achieved by assessing the ability of vitreally implanted MSCs to retard or prevent retinal degeneration in a mouse model of a form of neuronal ceroid lipofuscinosis (NCL), known as CLN1. This disease results from a mutation in a gene encoding a soluble lysosomal enzyme (PPT1) that is normally exchanged between cells. We hypothesize that if donor MSCs expressing normal or higher than normal levels of the PPT1 enzyme can take up long-term residence in the eye, they will supply enough of the enzyme to host retinal cells to prevent loss of host cell function and host cell death. We will test this hypothesis by conducting experiments to achieve the following specific aims: (1) Determine the long-term fate of normal MSCs transplanted into the vitreous of CLN1 knockout mice. (2) Determine whether donor MSCs can retard or prevent disease-related phenotypic changes in the CLN1 knockout mouse retina. (3) Determine whether the donor MSC effect is due to transfer the PPT1 protein to cells of the host mouse retina. By evaluating this approach in the mouse model, we will be in a better position to determine whether such an approach should be tested in humans. The mouse studies will provide valuable insights to guide the design of our future clinical studies in human patients. Successful outcomes of these studies could set the groundwork for using MSC implantation as a means of treating many retinal and other ocular diseases. Among the conditions that could potentially benefit from such an approach are eye diseases in which sustained delivery of a therapeutic agent by implanted cells would be beneficial. If successful, this approach could also be extended for treating neurodegenerative disorders that affect other parts of the central nervous system. PUBLIC HEALTH RELEVANCE: Studies will be undertaken to determine whether genetically modified stem cells isolated from the bone marrow can be used as vehicles for long-term, sustained delivery of therapeutic agents to eye tissues of people with a variety of retinal diseases. This approach to therapy will be tested be evaluating the ability of intraocular implantation of appropriately modified bone marrow stem cells to preserve the retina in animals with inherited diseases that cause retinal degeneration. The results of these studies will be relevant to the treatment of diseases such as age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, and many other disorders affecting the retina and other tissues as well.